P489: PROGNOSTIC IMPACT OF “MULTI-HIT” VERSUS “SINGLE-HIT” TP53 MUTATION IN PATIENTS WITH ACUTE MYELOID LEUKEMIA: RESULTS FROM THE CONSORTIUM ON MYELOID MALIGNANCIES AND NEOPLASTIC DISEASES (COMMAND)
Authors: Talha Badar, Ehab Atallah, Rory M. Shallis, Aaron D Goldberg, Ahmad Nanaa, Antoine Saliba, Anand Patel, Jan Bewersdorf, Adam Duvall, Madelyn Burkart, Danielle Bradshaw, Yasmin Abaza, Maximillian Stahl, Neil Palmisiano, Guru Subramanian Guru Murthy, Vamsi Kota, Amer M. Zeidan, Mark Litzow
Journal: HemaSphere (2023)

Background:TP53 mutated (m) acute myeloid leukemia (AML) is an adverse risk disease, often associated with prior cytotoxic therapy and complex cytogenetics. There are conflicting reports regarding the prognostic impact of allelic state, specifically bi-allelic alteration/ “multi-hit” (MH)TP53m (accompanying complex cytogenetic [CG] or loss of heterozygosity, multiple TP53m, single TP53m with variant allele frequency [VAF] >50% or 17p deletion) vs “single-hit” (SH)TP53m among patients (pts) with AML. Aims: We conducted a retrospective study through the COMMAND consortium (a collaboration of acute leukemia experts from 10 US academic institutions) to analyze the prognostic impact of MH versus (vs) SH TP53m on outcomes of adult (≥18 years) pts with AML. Methods: A total of 376 adult (SH [n= 58] and MH [n= 318]) pts with TP53m AML who were diagnosed between 2012-2022 were evaluated and their baseline characteristics, molecular profile, and treatment outcomes were compared based on SH vs MH TP53m status. Results: The median age was 68 (range [R], 23-88) and 66.5 (R,18-97) years in the SH and MH TP53m AML groups (gps) (p= 0.68), respectively (Table 1). Eight (20.5%) and 98 (31%) pts had secondary (s) AML in the SH and MH gps, respectively (p= 0.17). The median TP53m VAF (%) was 11 (R, 2-46) and 46 (R, 4-100) in the SH and MH TP53m AML gps (p= 0.005), respectively. Co-mutations were more frequently detected in the SH (89%) compared to the MH (58%) gp, respectively (p < 0.001). FLT3 (22% vs 2%, p= <0.001), ASXL1 (33% vs 7%, p= <0.001), TET2 (31% vs 11%, p= <0.001), RAS (29% vs 7%, p= <0.001), and splicing factor (20% vs 6%, p= 0.003) mutations were more frequent in the SH gp compared to the MH gp, respectively. A significantly higher proportion of pts received intensive chemotherapy (IC) in the SH gp (41% vs 22%, p= 0.002) and a higher proportion of pts in the MH gp received hypomethylating agents (HMA) plus venetoclax (VEN) (29% vs. 12%, p= 0.009). However, response rates (CR/CRi) were comparable between the SH and MH gps (24% vs 23%, p= 0.88). Similarly, a comparable proportion of pts received allogeneic stem cell transplant (allo-HCT) after induction (10% vs 14%; p= 0.45). The median duration of CR/CRi (8.0 vs 12.4, p= 0.51 [Figure A]) and event-free survival (EFS) (1.93 vs 2.83, p= 0.06 [Figure B]) was poorer in the MH, but this was not statistically significant (NS). However, median overall survival (OS) was significantly shorter in the MH gp (6.67 vs 20.0 months, p= 0.001 [Figure C]). We did multivariate analysis (MVA) for EFS and OS using baseline variables (Table 1) that showed significance/trend towards significance (p value ≤ 0.1) in univariate analysis. HMA plus VEN induction (HR; 0.58, 95% CI: 0.45-0.76, p= <0.001) and allo-HCT (HR; 0.25, 95% CI: 0.17-0.38, p= <0.001) retained significance for better EFS, whereas best supportive care (BSC) retained significance for shorter EFS (HR; 2.36, 95% CI: 1.57-3.53, p= <0.001). Allo-HCT after induction (HR; 0.19, 95% CI; 0.12-0.30, p= <0.001) retained favorable significance for OS, whereas MH TP53m (HR 2.72, 95% CI: 1.08-6.86, p= 0.03), TP53m with VAF > 10% (HR; 1.46, 95% CI: 1.07-2.0, p= 0.01) BSC (HR; 10.4, 95% CI: 6.62-16.5, p= <0.001) or other low intensity chemotherapy (HR; 2.54, 95% CI: 1.54-4.28, p= <0.001) retained significance for shorter OS in MVA. Summary/Conclusion: We observed distinct myeloid co-mutation patterns between SH vs MH TP53m AML. The OS was significantly shorter for pts with MH TP53m compared to SH TP53m. Prospective studies are needed to better understand the effect of MH TP53m on outcome of pts with AML.Keywords: Allogeneic bone marrow transplant, Acute myeloid leukemia, AML, TP53